Intrinsic diseases of the central nervous system (CNS), including the brain, the brainstem, the spinal cord and peripheral nerves, often result in serious morbidity, death or impairment of mobility because there is no effective surgical or medical therapy. Although an expanding number of potentially therapeutic compounds exist for treating these disorders, inadequate delivery of these agents to the CNS limits their effective use. Currently available delivery techniques rely on systemic or intrathecal drug administration, both of which have a number of inherent limitations. For example, systemic toxicity and the inability of many compounds to cross from the circulatory system to the CNS frequently restrict systemic delivery, and even if systemically delivered agents do enter the CNS, their distribution is either heterogeneous or non-targeted [see, for example, Langer, “New methods of drug delivery,” Science, 249:1527-1533 (1990); Morrison, “Distribution models of drug kinetics,” in Principles of Clinical Pharmacology, Atkinson et al (eds), Academic Press, New York, pp 93-112 (2001); and Pardridge, “Drug delivery to the brain.” J Cereb Blood Flow Metab, 17:713-731 (1997)]. Penetration into the nervous system following intrathecal delivery (including intrathecal injection, direct intratumoral injection, intracavitary instillation, or controlled release from polymer implants), like systemic delivery, relies on diffusion and also produces non-targeted, heterogeneous dispersion throughout the CNS [see, for example, Blasberg et al., “Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion,” J Pharmacol Exp Ther, 195:73-83 (1975)]. Potentially therapeutic substances have yet to be effective in the treatment of intrinsic diseases of the CNS due to the limitations of these delivery methods.
Convection-enhanced delivery (CED) may be used to overcome some of the restrictions associated with other delivery systems. CED utilizes a pressure gradient to infuse substances directly into the interstitial space of a solid tissue (interstitial infusion). Since CED relies on bulk (convective) flow, rather than diffusion, it can be used to distribute both small and large molecular weight substances over clinically relevant volumes within solid tissue [see, for example, Morrison et al., “Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics,” Am J Physiol, 277: R1218-1229 (1999) and Morrison et al., “High-flow microinfision: tissue penetration and pharmacodynamics,” Am J Physiol, 266: R292-305 (1994)]. Furthermore, substances are delivered at relatively constant concentration throughout the volume of distribution.
Factors that influence delivery of a therapeutic agent by CED include the type of tissue infused (for example, white or gray matter) and the tissue binding properties, metabolism and microvascular permeability of the agent. In addition, the volumetric flow rate, duration of infusion, and the size of the cannula (or catheter) used to deliver an infusate may affect the distribution of therapeutic agents delivered by CED.
Of particular concern during CED is retrograde flow (backflow) along the shaft of the cannula that is used to deliver the infusate to a tissue. Backflow may cause infused therapeutic agents to reach unintended tissue, and cause underexposure of the intended target. Theoretical studies of the factors affecting backflow indicate that it may be minimized by using a small diameter cannula, and that minimal backflow may be maintained by offsetting an increase in flow rate with a similar decrease in cannula radius. However, control of backflow remains a concern, particularly if CED is used in a clinical setting.
Furthermore, while a number of studies of CED have shown that there is a roughly linear relationship between the volume of infusate delivered (volume of infusion) and the volume over which the infusate is ultimately distributed (volume of distribution), they also show that other factors that influence the spread of an agent delivered by CED may not always be known for a given subject. These factors include existence of preferential pathways for fluid flow in the target region (for example, fiber tracts in white matter) which may lead to asymmetrical agent distribution, variable cell receptor density that may affect the timing and extent of an agent's spread, and large target volumes that may require long infusion times or multiple sites of delivery.
Single photon emission computed tomography (SPECT) has been applied to visualize the spread of an agent delivered by CED, but the method does not offer sufficient resolution to provide details of agent distribution [see, for example, Laske et al., “Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging,” J. Neurosurgery, 87: 586-594 (1997)]. As such, SPECT provides only an estimate of the volume of distribution and no detailed information about the shape of the infusion envelope in the tissue.
Since many therapeutic agents, especially those used to destroy tissue, such as cancer tissue, are highly toxic, control over the site of delivery during CED is especially important in the clinical setting, where minimization of side effects is a concern. A method that enables more precise control over the CED process would help ensure proper delivery of therapeutic agents to target regions of tissue without exposure of surrounding tissue to the agents. Such a method would fill a long-felt and heretofore unmet need in the art.